The invention concerns an analysis device for determining an analytic substance in the body of a patient (human or possibly animal) having a measuring probe comprising a hollow needle which can pierce through the skin.
The concentration of components of body fluids (analytes) is almost exclusively determined, in medical applications, by means of reagents. Towards this end, a sample of the body fluid (in particular blood) is taken and analyzed in the laboratory in vitro. The methods are being continuously improved and small hand-held analysis systems have meanwhile become available for important analytes, in particular blood glucose. The methods nevertheless have the disadvantage that each individual investigation requires the removal of blood and continuous measurements are not possible.
Fiber optic chemical sensors (FOCS) are known in the art for continuous measurement via immersion in a sample liquid. The absorption or luminescence of an indicator molecule is thereby observed via an optical fiber, the indicator molecule being localized on the tip of the optical fiber or in a jacket surrounding same. FOCS have also been used for continuous measurements of analytes in the blood of a patient, e.g. using a catheter introduced into the vein. Devices of this type are described in the following publications:
a) U.S. Pat. No. 5,127,077
b) EP 0 589 862 A2
c) U.S. Pat. No. 4,846,548
Efforts have been made for a long period of time to develop primarily based on spectroscopic principles reagent free analysis procedures. Conventional absorption spectroscopy using a transmission measurement is, however, in the major part of the spectrum not possible in blood, since blood contains strongly absorbing substances (in particular hemoglobin) which cover the characteristic spectral bands of the analytes being sought. Even if one removes the hemoglobin using a centrifuge, a strong interfering optical absorption remains in the particularly interesting regions of the infrared spectrum.
For this reason the possibility of using ATR (Attenuated Total Reflection) spectroscopy for investigation of aqueous biological liquids, in particular blood, has been studied. Reference is made to the following publications:
1) Y. Mendelson: xe2x80x9cBlood Glucose Measurement by Multiple Attenuated Total Reflection and Infrared Absorption Spectroscopyxe2x80x9d, IEEE Transactions on Biomedical Engineering, 1990, 458-465.
2) H. M. Heise et al.: xe2x80x9cMulti component Assay for Blood Substrates in Human Plasma by Mid-infrared Spectroscopy and its Evaluation for Clinical Analysisxe2x80x9d, Applied Spectroscopy 1994, 85 to 95.
3) R. Simhi et al.: xe2x80x9cMulti-component Analysis of Human Blood Using Fiber Optic Evanescent Wave Spectroscopyxe2x80x9d, SPIE Proc. Vol. 2331: Medical Sensors II and Fiber Optic Sensors Sep. 6-Sep. 10, 1994, Lille, France, A. V. Scheggi et al. (Eds.), ISBN 0-8194-1664-9, published 1995, pages 166 to 172.
These references show that it is, in principle, possible to use ATR spectroscopy to detect important analytes, in particular glucose, in blood reagent free by spectroscopic means. In ATR spectroscopy, light is transported through a light guide whose outer surface is in contact with the sample. The index of refraction within the light guide (relative to the index of refraction of the sample) and the angles of reflection of the light at the boundary must be selected such that the light is totally internally reflected. Total internal reflection comprises penetration of an evanescent wave into the neighboring medium (the sample). The absorption which thereby occurs leads to an attenuation of the intensity of the light transported in the light guide. This attenuation in intensity can be evaluated as a function of wavelength in order to extract information from the spectrum concerning the presence of the analyte in the sample. Further details can be taken from the relevant literature, in particular, 1) to 3) cited above.
ATR measurements generally utilize special ATR measuring cells with a light guide having a prismatic shape. Alternatively, fiber optic light guides have been frequently proposed. An example, with regard to medical analysis of blood components, is reference 3).
The publication
4) U.S. Pat. No. 5,436,454,
describes a device which allegedly enables ATR spectroscopy of blood of a patient in vivo. Towards this end, a thin hollow needle, similar to an injection needle, can be introduced through the skin of the patient into a blood vessel for in vivo measurements. A thin optical fiber passes through the hollow needle up to the tip thereof and is bent at this location back in the opposite direction in a narrow loop to travel back through the hollow needle. A light guide leg passing through the hollow needle transports measuring light to the loop. A second leg passes the light back to a detector. The hollow needle has a diameter of approximately 3 mm and an inner bore of approximately 2 mm for acceptance of the optical fibers having a diameter of 0.7 mm to 1 mm. The publication discloses that many more reflections of the light transported in the light guide occur in the region of the loop than in the straight sections. As a result thereof, a substantially higher sensitivity is present in the loop region. In the measurement state, the loop protrudes somewhat past the tip of the hollow needle and a seal prevents the sample from penetrating into the hollow needle. The measurement is thereby confined solely to the region of the loop. The measurement is intended to be carried out in a spectral region having wave numbers between 7,000 and 700 (corresponding to 1.5 to 15 xcexcm). Chalcogenic glass is proposed as a material for the optical fibers.
Another example of a publication concerned with ATR spectroscopy for in vivo analysis of body components, in particular glucose, is
5) WO 91/18548.
A further measurement concept, namely the measurement of the index of the refraction, is recommended for measuring glucose in blood in
6) WO 90/101697.
On the basis of this prior art, it is an object of the invention to provide an improved analysis device for determination of an analyte in vivo in the body of the patient.
This purpose is achieved using an analysis device for the determination of an analyte in vivo in the body of a patient, including a measuring probe comprising a hollow needle for puncturing into the skin and with an optical fiber travelling through the hollow needle by means of which light emanating from a light source and coupled into the optical fiber can be guided through the hollow needle to the measuring probe which is pierced into the skin and thus into the body, wherein the light in the measuring probe transported through the optical fiber undergoes, through direct reagent free interaction with interstitial liquid surrounding the optical fiber within in the body, a change characterizing the presence of the analyte and having a measurement and evaluation unit for measuring the change and for deriving, from this change, information concerning the presence of the analyte in the body, characterized in that the hollow needle is permeable through at least a partial section of its length which penetrates into the skin and which serves as a measuring section, so that the interstitial liquid passes through the hollow needle wall and gains access to a measuring section of the optical fiber extending in the hollow needle, and the change in the light characterizing the presence of the analyte results from interaction with the interstitial liquid in the measuring section.
It has been discovered within the context of the invention that in contrast to the recommendation of publication 4) the measurement is advantageously not concentrated at a loop at the tip of the hollow needle. Rather it is carried out along a longer measuring section of preferentially at least 2 mm and particularly preferentially between 3 mm and 10 mm of length within a hollow needle which can be penetrated along the length of this measuring section. The measuring medium is not blood in a vein but rather the interstitial liquid in skin tissue, preferentially in subcutaneous skin tissue. An improved precision and sensitivity is thereby achieved. Among other reasons, it has been discovered in accordance with the invention that a highly localized measurement is associated with a high risk of measurement error due to local irregularities both with regard to the measuring probe as well as with regard to the surrounding skin tissue. In contrast to the FOCS, the analysis is based on the direct reagent-free interaction along the measuring section of the light transported through the optical fiber with the sample liquid.
The measuring section of the hollow needle is sufficiently permeable to the interstitial liquid that the interaction of the light transported in the optical fiber with the analyte which is required for the analysis takes place in the measuring section. Within the context of the invention, it has been discovered that, with the very small dimensions of the hollow needle, diffusion exchange of the analyte between the interstitial liquid surrounding the hollow needle and the surface of the optical fiber in the measuring section is sufficient to allow monitoring of the physiological changes of important analytes, in particular glucose, with high precision. The permeability of the hollow needle must be adapted to this requirement. In the preferred case of a metallic hollow needle, the permeability is effected by appropriate perforations.
In addition to metal, a sufficiently stiff plastic would also, in principle, be suitable for making the needle. In such embodiment the required permeability may result from the structure of the plastic material itself, i.e. a material can be utilized which is permeable to the analyte molecules without subsequent introduction of holes, due to its manufacturing and material properties.
Goals of the invention, in particular to allow measurement precision while maintaining patient acceptance for continuous measurements over long periods of time (at least one day and preferentially three days), can be better achieved when the following preferred features are utilized individually or in combination with each other.
A preferred measurement principle is based on the interaction between the light and the analyte in the measuring section caused by the penetration of an evanescent field into the liquid, in particular based on ATR spectroscopy. Thus the wavelength dependent attenuation in the measuring section is the modification of the light transported in the optical fiber which is characteristic of the presence of the analyte. Concerning suitable measurement and evaluation procedures, reference is made to the complete disclosure of the relevant literature, in particular to the publications cited above.
The wavelength of the measuring light is preferentially in the mid-infrared (MIR), in particular between approximately 7 xcexcm and 13 xcexcm. This wavelength region is particularly suitable for the analysis of glucose as the analyte.
The optical fiber material should in the spectral region of the measuring light be as transparent as possible. A silver halide compound, in particular AgCl, AgBr or mixtures thereof, are particularly suitable to achieve the purpose of the invention. Particularly preferred are mixtures having a predominant fraction of AgBr. These materials have very low absorption in the relevant spectral region and can be produced in the form of very thin elastic fibers. A potential problem associated with their use in contact with body liquids is that body liquids always contain substantial concentrations of ions which can corrode the silver halide compound. Within the context of the invention, it has however been determined that silver halide fibers, in particular in the above mentioned wavelength regions, can be used for a period of several days in direct contact with the interstitial liquids without additional protective measures and without having their function being impaired to a significant extent by corrosion.
Use of silver halide fibers for non-medical analysis is e.g. disclosed in the following literature:
7) R. Goebel et al.: xe2x80x9cEnhancing the Sensitivity of Chemical Sensors for Chlorinated Hydrocarbons in Water by the Use of Tapered Silver Halide fibers and Tunable Diode Lasersxe2x80x9d, Applied Spectroscopy, 1995, 1174 to 1177.
8) J. F. Kastner et al.: xe2x80x9cOptimizing the Optics for Evanescent Wave Analysis with Laser Diodes (EWALD) for Monitoring Chlorinated Hydrocarbons in Waterxe2x80x9d, SPIE vol. 2783 (1996), 294 to 306.
9) DE 40 38 354 C2
A further material for the optical fibers (preferred to a lesser extent) could be chalcogenic glass.
Most recently, synthetic diamonds can also be produced in the form of suitable fibers. For the present invention, a relatively short, very thin piece of optical fiber material is sufficient. In the case of diamond, the fiber preferentially has, for manufacturing reasons, a quadratic or rectangular cross section. This synthetic diamond material is preferentially produced by layered deposition from the gas phase, in particular, using chemical vapor deposition (CVD). A thin xe2x80x9cneedlexe2x80x9d can be fashioned from the formed layer, as will be described below. The optical properties of diamond in the relevant infrared wavelength region of the light are not as good as those of the above mentioned fiber materials. The transmission is however sufficient for making the measurement. The diamond material has the particular advantage of being corrosion resistant to, among others, salt-containing solutions. Further details can be taken from German patent application 19734617.0 filed on Aug. 9, 1997 entitled xe2x80x9cDevice for the Investigation of a Sample Substance Using Attenuated Total Internal Reflectionxe2x80x9d, the complete disclosure of which is hereby incorporated by reference.
Germanium and silicon are additional materials suitable for the light guide. These materials, with high purity, have good transmission properties for IR light (for example, Ge lenses are utilized for IR cameras). Since the micro mechanics for processing these materials has been highly developed, the thin needles required within the framework of the invention can be manufactured in an acceptable fashion. Although their high index of refraction creates problems for coupling the light into the needle, the intensity losses associated therewith are acceptable.
Within the framework of the invention, the optical fibers must not, in general, have a round cross section. The expression xe2x80x9cfiberxe2x80x9d is to be understood as a piece of light guiding material having a length sufficient for insertion through the skin along the required length of the hollow needle (at least approximately 3 mm) and having a cross section which is very small relative to its length. The hollow needles should preferentially have an outer diameter of at most 0.8 mm, and particularly preferred, of at most 0.5 mm or even 0.3 mm. Assuming a wall thickness of 0.05 mm, the associated inside cross section has a diameter of 0.7 mm, 0.5 mm, or 0.2 mm respectively. The cross section of the fiber must be such that it passes through this small lumen of the hollow needle. Should the fiber be non-round in shape, the hollow needle can also have a corresponding non-round cross section.
Additional preferred embodiments, described in more detail with regard to the embodiments shown in the figures, provide for the following features:
The cross section of the optical fiber in the measuring section is not constant, rather varies. There is one or are a plurality of transitions between a larger optical fiber cross section and a smaller optical fiber cross section. In this manner, (as described in a different context in the above mentioned publications) the number of reflections in the optical fiber and therefore the sensitivity of the measurement is increased.
The optical fiber is jacketed within a semi-permeable membrane in such a manner that the interstitial liquid in the measuring section can only penetrate to the surface of the optical fiber through the membrane. The semi-permeable membrane has a cut-off for large molecules having a molecular size in excess of 5,000 Da, preferentially for molecules having a molecular size in excess of 1,000 Da. The cut-off should be as sharp as possible and the permeability rate for smaller molecules should be as high as possible. The membrane leads to an increase in the precision for a given degree of measuring effort. Alternatively, a desired measuring precision can be achieved more easily. Protein deposits on the surface of the light guide and other interfering effects associated with large molecules are avoided. For example, the number of wavelengths required for analysis can be reduced. Moreover, the semi-permeable membrane reduces rejection of the probe penetrating into the skin by the body. As a result, the length of time of use inside the body can be extended. In particular, polysulfone, polyamide, polyethylene, polycarbonate and cellulose can be utilized as a material for the membrane.
The optical fiber is provided in the measurement region with a coating which may serve a plurality of purposes. On the one hand, it can protect the fibers from corrosion. In addition, it can constitute a spacer to prevent direct contact between the optical fiber and a semi-permeable membrane jacket. A material can be chosen for the coating which leads to an enrichment of the analyte at the surface of the optical fiber.